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Milroy Disease (Lymphedema Type I) via the FLT4 Gene

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
FLT4 81479 81479,81479 $990
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
11339FLT481479 81479,81479 $990 Order Options and Pricing

Pricing Comments

Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information. If the Sanger option is selected, CNV detection may be ordered through Test #600.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

Click here for costs to reflex to whole PGxome (if original test is on PGxome Sequencing platform).

Click here for costs to reflex to whole PGnome (if original test is on PGnome Sequencing platform).

The Sanger Sequencing method for this test is NY State approved.

For Sanger Sequencing click here.

Turnaround Time

3 weeks on average for standard orders or 2 weeks on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.


Genetic Counselors


  • Siwu Peng, PhD

Clinical Features and Genetics

Clinical Features

Lymph is a clear-to-white interstitial fluid comprised primarily of white blood cells, proteins, and lipids. The lymphatic system is a subset of the circulatory system with vessels and nodes that transport lymph throughout the body and includes the tonsils, adenoids, spleen, and thymus. The primary functions of the lymphatic system include ridding the body of infection and maintaining fluid balance. Improper lymphatic function can lead to lymph accumulation and swelling known as lymphedema. Lymphedema can result in infections and other complications including a form of lymphatic cancer called lymphangiosarcoma. Primary lymphedema is caused by pathologic development of the lymphatic system. Secondary lymphedema can arise from other conditions or disease treatments; most commonly from cancer and cancer treatments including lymphadenectomy (Gordon and Mortimer 2007; Warren et al. 2007). Milroy Disease (also known as Lymphedema Type I) is a type of primary lymphedema characterized by edema of the lower limbs (Brice et al. 2005). The swelling is typically bilateral, localized below the knee, and is often present at birth or develops in early infancy. Ultrasound showing in utero pleural effusions, lower limb swelling, and hydrops fetalis has also been used for prenatal diagnosis of Milroy disease (Daniel-Speigel et al. 2005; Ghalamkarpour et al. 2006). Other common features of Milroy disease include hydrocele in male patients, cellulitis, upslanting toenails, papillomas, and hyperkeratosis.


Milroy disease displays primarily autosomal dominant inheritance and is estimated to occur in 1:6000 births (Witte et al. 1998). At least two cases of apparent autosomal recessive inheritance have also been reported (Ghalamkarpour et al. 2009; Melikhan-Revzin et al. 2015). Variants in the FLT4 gene (also known as VEGFR3) are the only known cause of Milroy disease (Iljin et al. 2001; Evans et al. 2003; Brice et al. 2005). FLT4 encodes Vascular Endothelial Growth Factor Receptor 3 (VEGFR3) a receptor tyrosine kinase found in lymphatic endothelial cells (Kaipainen et al. 1995). VEGFR3 is activated by the ligands VEGF-C and VEGF-D during lymphangiogenesis (Veikkola et al. 2001). Nearly all pathogenic variants are found in one of the two tyrosine kinase domains indicating the importance of these domains for VEGFR3 protein function during proper lymphatic system development (Ferrel et al. 1998, Evans et al. 2003; Ghalamkarpour et al. 2006). Pathogenic variants comprise mostly missense and nonsense variants, however at least one splice site variant and a few small deletions have also been reported. To date, no large deletions or duplications in the FLT4 gene have been reported in patients with Milroy disease. Penetrance of causative FLT4 variants appears to be 80-84% (Ferrell et al. 1998; Evans et al. 1999). At least one variant outside of the tyrosine kinase domains has been reported in patients with FLT4-related disorders that may have recessive inheritance (Melikhan-Revzin et al. 2015).

Clinical Sensitivity - Sequencing with CNV PGxome

This test covers 100% of the coding region of the FLT4 gene. Variants in the FLT4 gene are the only known cause of Milroy disease. To date, pathogenic variants in 7 genes have been associated with disorders having lymphedema as a primary symptom, however, the extent to which each of the 7 known primary lymphedema genes contribute to the overall rate of primary lymphedema is unclear. Lymphedema is also a secondary symptom of many other disorders.

To date, no large deletions or duplications in the FLT4 gene have been reported in patients with Milroy disease.

Testing Strategy

This test provides full coverage of all coding exons of the FLT4 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).

Indications for Test

Candidates for this test are patients with symptoms consistent with primary lymphedema or Milroy Disease, and the family members of patients with known variants.


Official Gene Symbol OMIM ID
FLT4 136352
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
Hereditary Lymphedema Type I AD 153100


  • Brice G. 2005. Journal of Medical Genetics. 42: 98-102. PubMed ID: 15689446
  • Daniel-Spiegel E. et al. 2005. Prenatal Diagnosis. 25: 1015-8. PubMed ID: 16231305
  • Evans A.L. et al. 1999. American Journal of Human Genetics. 64: 547-55. PubMed ID: 9973292
  • Evans A.L. et al. 2003. Journal of Medical Genetics. 40: 697703. PubMed ID: 12960217
  • Ferrell R.E. et al. 1998. Human Molecular Genetics. 7: 2073-8. PubMed ID: 9817924
  • Ghalamkarpour A. et al. 2006. Clinical Genetics. 70: 330-5. PubMed ID: 16965327
  • Ghalamkarpour A. et al. 2009. Journal of Medical Genetics. 46: 399-404. PubMed ID: 19289394
  • Gordon and Mortimer. 2007. A Guide to Lymphedema.
  • Iljin K. et al. 2001. The Faseb Journal. 15: 102836. PubMed ID: 11292664
  • Melikhan-Revzin S. et al. 2015. Lymphatic Research and Biology. 13: 107-11. PubMed ID: 26091405
  • Veikkola T. et al. 2001. The Embo Journal. 20: 1223-31. PubMed ID: 11250889
  • Warren A.G. et al. 2007. Annals of Plastic Surgery. 59: 464-72. PubMed ID: 17901744
  • Witte M.H. et al. 1998. Lymphology. 31: 145-55. PubMed ID: 9949386


Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page

If ordering a Duo or Trio test, the proband and all comparator samples are required to initiate testing. If we do not receive all required samples for the test ordered within 21 days, we will convert the order to the most effective testing strategy with the samples available. Prior authorization and/or billing in place may be impacted by a change in test code.

Specimen Types

Specimen Requirements and Shipping Details

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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View Ordering Instructions

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2) Select Additional Test Options

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Note: acceptable specimen types are whole blood and DNA from whole blood only.
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